1. Field of the Invention
This invention is in the field of medicinal chemistry. In particular, the invention relates to novel substituted semicarbazides and the discovery that these compounds are anticonvulsants and act as blockers of sodium (Na.sup.+) channels.
2. Related Background Art
Several classes of therapeutically useful drugs, including local anesthetics such as lidocaine and bupivacaine, antiarrhythmics such as propafenone and amioclarone, and anticonvulsants such as lamotrigine, phenytoin and carbamazepine. have been shown to share a common mechanism of action by blocking or modulating Na.sup.+ channel activity (Catterall, W. A., Trends Pharmacol. Sci. 8:57-65 (1987)). Each of these agents is believed to act by interfering with the rapid influx of Na.sup.+ ions.
Recently, other Na.sup.+ channel blockers such as BW619C89 and lifarizine have been shown to be neuroprotective in animal models of global and focal ischemia and are presently in clinical trials (Graham et al., J. Pharmacol. Exp. Ther. 269:854-859 (1994); Brown et al., British J. Pharmacol. 115:1425-1432 (1995); SCRIP 1870:8 (1993); SCRIP 1773:14 (1992)).
The neuroprotective activity of Na.sup.+ channel blockers is due to their effectiveness in decreasing extracellular glutamate concentration during ischemia by inhibiting the release of this excitotoxic amino acid neurotransmitter. Studies have shown that unlike glutamate receptor antagonists, Na.sup.+ channel blockers prevent hypoxic damage to mammalian white matter (Stys et al., J. Neurosci. 12:430-439 (1992)). Thus, they may offer advantages for treating certain types of strokes or neuronal trauma where damage to white matter tracts is prominent.
Another example of clinical use of a Na.sup.+ channel blocker is riluzole. This drug has been shown to prolong survival in a subset of patients with ALS (Bensimm et al., New Engl. J. Med. 330:585-591 (1994)) and has subsequently been approved by the FDA for the treatment of ALS. In addition to the above-mentioned clinical uses, carbamazepine, lidocaine and phenytoin are occasionally used to treat neuropathic pain, such as from trigeminal neurologia, diabetic neuropathy and other forms of nerve damage (Taylor and Meldrum, Trends Pharmacol. Sci. 16:309-316 (1995)), and carbamazepine and lamotrigine have been used for the treatment of manic depression (Denicott et al., J. Clin. Psychiatry 55: 70-76 (1994)).
It has been established that there are at least five to six sites on the voltage-sensitive Na.sup.+ channels which bind neurotoxins specifically (Catterall, W. A., Science 242:50-61 (1988)). Studies have further revealed that therapeutic antiarrhythmics, anticonvuisants and local anesthetics whose actions are mediated by Na.sup.+ channels, exert their action by interacting with the intracellular side of the Na.sup.+ channel and allosterically inhibiting interaction with neurotoxin receptor site 2 (Catterall, W. A., Ann. Rev. Pharmacol. Toxicol. 10:15-43 (1980)).
PCT International Published Application WO96/40628 discloses semicarbazones represented by the following Formula: ##STR2##
where R.sub.1 -R.sub.4 are independently hydrogen, halogen, C.sub.1-9 alkyl, C.sub.3-9 cycloalkyl, cyano, C.sub.1-9 alkoxy, or C.sub.6-10 aryloxy; R.sub.5 is hydrogen, C.sub.1-9 alkyl, C.sub.3-9 cycloalkyl, or C.sub.6-10 aryl; and X is oxygen or sulfur. The compounds are disclosed to be useful as anticonvulsants. However, it was not suggested or implicated that semicarbazides, which can be prepared by reduction of the semicarbazones, also will act as anticonvulsants.
Dimmock et al., J. Med. Chem. 39:3984-3997 (1996) discloses (aryloxy)aryl semicarbazones that displayed anticonvulsant activities when administered intraperitoneally to mice or orally to rats. However, it was not suggested or implicated that semicarbazides, which can be prepared by reduction of the semicarbazones, also will act as anticonvulsants.